1. Field of the Invention
The present invention relates generally to the field of cancer biology. More specifically, the present invention discloses methods of treating human multiple myeloma by curcumin.
2. Description of the Related Art
Multiple myeloma is a B cell malignancy characterized by the latent accumulation in bone marrow of secretory plasma cells with a low proliferative index and an extended life span. Multiple myeloma accounts for 1% of all cancers and >10% of all hematologic cancers. Standard treatment regimen includes a combination of vincristine, BCNU, melphalan, cyclophosphamide, Adriamycin, and prednisone or dexamethasone. Despite treatment with large doses of glucocorticoids and alkylating agents, this malignancy remains incurable. Complete remission rate is 5% and median survival is 30–36 months. In more than 90% of the patients, the disease becomes chemoresistant. Therefore, safe and efficacious agents are urgently needed for treatment of multiple myeloma.
Dysregulation of apoptotic mechanisms in plasma cells is considered a major underlying factor in the pathogenesis and subsequent chemoresistance in multiple myeloma. It is established that IL-6, produced in either an autocrine or paracrine manner, has an essential role in the malignant progression of multiple myeloma by regulating the growth and survival of tumor cells. The presence of IL-6 leads to constitutive activation of Stat 3 which in turn results in expression of high levels of anti-apoptotic protein Bcl-xL. Bcl-2 overexpression, another important characteristic of the majority of multiple myeloma cell lines, rescues these tumor cells from glucocorticoid-induced apoptosis. Treatment of multiple myeloma cells with TNF activates NF-κB, induces secretion of IL-6, induces expression of various adhesion molecules and promotes proliferation. Furthermore, multiple myeloma cells have been shown to express the ligand for the receptor that activates NF-κB (RANKL), a member of the TNF superfamily which could mediate multiple myeloma-induced osteolytic bone disease.
One of the potential mechanisms by which multiple myeloma cells could develop resistance to apoptosis is through the activation of nuclear transcription factor NF-κB. Under normal conditions, NF-κB is present in the cytoplasm as an inactive heterotrimer consisting of p50, p65, and IκBα subunits. Upon activation, IκBα undergoes phosphorylation and ubiquitination-dependent degradation by the 26S proteosome, thus exposing nuclear localization signals on the p50–p65 heterodimer, leading to nuclear translocation and binding to a specific consensus DNA sequence (5′-GGGACTTTC-3′, SEQ ID NO. 1). NF-κB binding to DNA activates gene expression that in turn results in gene transcription. Phosphorylation of IκBα occurs through the activation of IκB kinase (IKK). The IκB kinase complex consists of three proteins IKKa, IKKb and IKKg/NF-kB essential modulator (NEMO). IKKα and IKKβ are the kinases that are capable of phosphorylating IκBα, whereas IKKγ/NEMO is a scaffold protein that is critical for IKKα and IKKβ activity.
Extensive research during the past few years has indicated NF-κB regulates the expression of various genes that play critical roles in apoptosis, tumorigenesis, and inflammation. Some of the NF-κB-regulated genes include IκBα, cyclin D1, Bcl-2, bcl-xL, COX-2, IL-6, and adhesion molecules ICAM-1, VCAM-1, and ELAM-1. Recently it was reported that NF-κB is constitutively active in multiple myeloma cells, leading to bcl-2 expression that rescues these cells from glucocorticoid-induced apoptosis. Since multiple myeloma cells express IL-6, various adhesion molecules, Bcl-xL, and Bcl-2 which are all regulated by NF-κB, and since their suppression can lead to apoptosis, it is proposed that NF-κB is an important target for multiple myeloma treatment. However, the prior art is deficient in identifying a pharmacologically safe and effective agent with which to block constitutive NF-κB in multiple myeloma. The present invention fulfills this long-standing need in the art.